1. Field of the Invention
This invention is in the field of medicinal chemistry. The invention relates to novel azetidinyl, pyrrolidinyl, piperidinyl, and hexahydroazepinyl compounds and the discovery that these compounds act as blockers of calcium (Ca2+) channels.
2. Background Art
Calcium ions play fundamental roles in the regulation of many cellular processes. It is therefore essential that their intracellular levels be maintained under strict, yet dynamic control (Davila, H. M., Annals of the New York Academy of Sciences, pp. 102-117 (1999)). Voltage-gated calcium channels (VGCC) serve as one of the important mechanisms for fast calcium influx into the cell. Calcium channels are hetero-oligomeric proteins consisting of a pore-forming subunit (α1), which is able to form functional channels on its own in heterologous expression systems, and a set of auxiliary or regulatory subunits. Calcium channels have been classified based on their pharmacological and/or electrophysiological properties. The classification of voltage-gated calcium channels divides them into three groups: (i) high voltage-activated (HVA) channels, which include L-, N-, P-, and Q-types; (ii) intermediate (IVA) voltage-activated R-type channels; and (iii) low voltage-activated (LVA) T-type channels (Davila, supra). Voltage-gated calcium channels (VGCC) are also known as voltage-dependent calcium channels (VDCC) or voltage-sensitive calcium channels (VSCC).
Voltage-sensitive calcium channels (VSCC) regulate intracellular calcium concentration, which affects various important neuronal functions such as cellular excitability, neurotransmitter release, hormone secretion, intracellular metabolism, neurosecretory activity and gene expression (Hu et al., Bioorganic & Medicinal Chemistry 8:1203-1212 (2000)). N-type channels are found mainly in central and peripheral neurons, being primarily located on presynaptic nerve terminals. These channels regulate the calcium flux required for depolarization-evoked release of a transmitter from synaptic endings. The transmission of pain signals from the periphery to the central nervous system (CNS) is mediated by N-type calcium channels located in the spinal cord (Song et al, J. Med. Chem. 43:3474-3477 (2000)).
The six types of calcium channels (i.e., L, N, P, Q, R, and T) are expressed throughout the nervous system (Wallace, M. S., The Clinical Journal of Pain 16:580-585 (2000)). Voltage-sensitive calcium channels of the N-type exist in the superficial laminae of the dorsal horn and are thought to modulate nociceptive processing by a central mechanism. Blockade of the N-type calcium channel in the superficial dorsal horn modulates membrane excitability and inhibits neurotransmitter release, resulting in pain relief. Wallace (supra) suggests that based on animal models, N-type calcium channel antagonists have a greater analgesic potency than sodium channel antagonists.
N-type calcium channel blockers have usefulness for neuroprotection and analgesia. Ziconotide, which is a selective N-type calcium channel blocker, has been found to have analgesic activity in animal models and neuroprotective activity in focal and global ischemia models (Song et al., supra). Examples of known calcium channel blockers include flunarizine, fluspirilene, cilnipide, PD 157767, SB-201823, SB-206284, NNC09-0026, and PD 151307 (Hu et al., supra).
Blockade of N-type channels can prevent and/or attenuate subjective pain as well as primary and/or secondary hyperalgesia and allodynia in a variety of experimental and clinical conditions (Vanegas, H. et al., Pain 85:9-18 (2000)). N-type voltage-gated calcium channels (VGCC) play a major role in the release of synaptic mediators such as glutamate, acetylcholine, dopamine, norepinephrine, gamma-aminobutyric acid (GABA) and calcitonin gene-related peptide (CGRP).
Inhibition of voltage-gated L-type calcium channels has been shown to be beneficial for neuroprotection (Song et al., supra). However, inhibition of cardiac L-type calcium channels can lead to hypotension. It is believed that a rapid and profound lowering of arterial pressure tends to counteract the neuroprotective effects of L-type calcium channel blockers. A need exists for antagonists that are selective for N-type calcium channels over L-type calcium channels to avoid potential hypotensive effects.
Published PCT Application No. WO 02/28346 by Odile et al. describes N-{1-[bis(4-chlorophenyl)methyl]-3-azetidinyl}-4-fluoro-N-methylbenzenesulfonamide and N-{1-[bis(4-chlorophenyl)methyl]-3-azetidinyl}-N-methylbenzenesulfonamide as CB 1 receptor antagonists. U.S. Pat. No. 6,262,046 to Alker et al describes 1-diphenylmethyl-3-(N-methylbenzenesulfonamido)azetidine as an intermediate.
U.S. Pat. No. 6,734,176 to Achard et al. describes pharmaceutical compositions containing 3-aminoazetidine derivatives useful as CB 1-receptor antagonists.
United States Patent Application Publication No. US 2004/00224901 by Chaturvedula et al. describes N-{1-[(2R)-2-amino-3-(4-chlorophenyl)propionyl]-(3S)-pyrrolidin-3-yl}-N-cyclohexyl-benzenesulfonamide and [2-[(3S)-3-(benzenesulfonyl-cyclohexylamino)pyrrolidin-1-yl]-(1R)-(4-chlorobenzyl)-2-oxo-ethyl]carbamic acid tert-butyl ester as intermediates.
United States Patent Application Publication No. US 2005/245573 by Neitzel et al. describes 4-chloro-N-ethyl-N-[1-(phenylmethyl)-3-pyrrolidinyl]benzenesulfonamide useful in the treatment of or prevention of congnitive disorders, such as Alzheimer's disease.